Process for producing α-aminoketone derivatives

ABSTRACT

A process for producing α-amino-dihalogenated methyl ketone derivatives by reacting an N-protected α-amino acid ester with a dihalomethyl lithium is provided. This process is suitable for the production on an industrial scale and by this process, α-amino-dihalogenated methyl ketone derivatives and β-amino-α-hydroxycarboxylic acid derivatives can be obtained efficiently and economically advantageously.

This application is a Continuation International ApplicationPCT/JP00/01498 filed on Mar. 13, 2000.

BACKGROUND OF THE INVENTION

The present invention relates to a process for producingα-amino-dihalogenated methyl ketone derivatives from N-protected α-aminoacid esters.

The present invention also relates to a process for producingβ-amino-α-hydroxycarboxylic acid derivatives from theα-amino-dihalogenated methyl ketone derivatives.

It was reported that α-amino-dihalogenated methyl ketone derivatives canbe easily converted into β-amino-α-hydroxycarboxylic acid derivatives byhydrolysis in the presence of a base (see J.P. KO-KAI No. Hei 10-59909).β-Amino-α-hydroxycarboxylic acid derivatives obtained by this reactionare important compounds as intermediates for inhibitors of enzymes, suchas HIV protease and renin or for some anticancer drugs (see, forexample, Chem. Pharm. Bull. 1992, 40, 2251, J. Med. Chem. 1990, 33,2707, Biochem. Pharmacol. 1983, 32, 1051, and Bull. Cancer 1993, 80,326).

As for processes for producing α-amino-dihalogenated methyl ketonederivatives, it is described in an Example of J.P. KOKAI No. Hei10-59909 that an N-carbamate-protected α-amino-dichloromethyl ketonederivative is produced by treating an α-amino-monochloromethyl ketonederivative, in which the amino group is protected with a carbamate-typeprotecting group, with sulfuryl chloride. However, this process isunsuitable for the production of a compound having a protecting group(such as t-butoxycarbonyl group) for an amino group, which is unstableagainst acids, because a strong acid is formed in the reaction system.In addition, the production of N-carbamate-protectedα-amino-monochloromethyl ketone derivatives used as the startingmaterial is not always easy.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide an economical,efficient process for producing α-amino-dihalogenated methyl ketonederivatives and β-amino-α-hydroxycarboxylic acid derivatives on anindustrial scale.

After intensive investigations made for the purpose of solving theabove-described problems, the inventors have found thatα-amino-dihalogenated methyl ketones can be easily obtained by reactingan N-protected α-amino acid ester with a dihalomethyl lithium. Thepresent invention has been completed on the basis of this finding.

Namely, the present invention provides a process for producingα-amino-dihalogenated methyl ketone derivatives of the following generalformula (3):

wherein B³ and B⁴ independently represent a hydrogen atom or aprotecting group for an amino group, or B³ and B⁴ together form animine-type protecting group; A represents a hydrogen atom, anunsubstituted or substituted alkyl group having 1 to 10 carbon atoms,aryl group having 6 to 15 carbon atoms or aralkyl group having 7 to 20carbon atoms, or a group corresponding thereto which contains a heteroatom in the carbon skeleton; and X¹ and X² independently represent achlorine atom or a bromine atom,

which comprises the step of reacting an N-protected α-amino acid esterof following general formula (1):

wherein B¹ and B² independently represent a hydrogen atom or aprotecting group for an amino group, or B¹ and B² together form animine-type protecting group (with the proviso that both B¹ and B² cannotbe hydrogen atom at the same time), R¹ represents an unsubstituted orsubstituted lower alkyl group, aralkyl group or aryl group, and A is asdefined above,

with a dihalomethyl lithium of general formula (2)

wherein X¹ and X² are as defined above.

The present invention also provides a process for producingβ-amino-α-hydroxycarboxylic acid derivatives of general formula (4):

wherein B⁵ and B⁶ independently represent a hydrogen atom or aprotecting group for an amino group, or B⁵ and B⁶ together form animine-type protecting group, and A represents hydrogen atom, anunsubstituted or substituted alkyl group having 1 to 10 carbon atoms,aryl group having 6 to 15 carbon atoms or aralkyl group having 7 to 20carbon atoms, or a group corresponding thereto which contains a heteroatom in the carbon skeleton,

which comprises the steps of hydrolyzing an α-amino-dihalogenated methylketone derivative in the presence of a base and protecting or notprotecting the amino group.

BEST MODE FOR CARRYING OUT THE INVENTION

In the formulae in the present invention, B¹ and B² independentlyrepresent a hydrogen atom or a protecting group for an amino group, orB¹ and B² together form an imine-type protecting group. However, both B¹and B² cannot be hydrogen atom at the same time.

The protecting group for amino group is not particularly limited. Forexample, protecting groups described in Protecting Groups in OrganicChemistry, 2^(nd) Edition (John Wiley & Sons, Inc. 1991) are usable. Theprotecting groups are, for example, carbamate-type protecting groupssuch as a methoxycarbonyl group, a ethoxycarbonyl group, at-butoxycarbonyl group, a benzyloxycarbonyl group, and afluorenylmethoxycarbonyl group; acyl-type protecting groups such as anacetyl group and a benzoyl group; sulfonyl-type protecting groups, suchas a methanesulfonyl group, a benzenesulfonyl group, and ap-toluenesulfonyl group; alkyl-type protecting groups, such as a benzylgroup and a p-methoxybenzyl group; dialkyl-type protecting groups, suchas, a dibenzyl group; silyl-type protecting groups, such as, atrimethylsilyl group; and imine-type protecting groups, such as, adiphenylmethylene group, a phenylmethylene group, and ap-methoxyphenylmethylene group. Among them, carbamate-type protectinggroups are preferred because they can be easily removed.

When B¹ and B² together form an imine-type protecting group, N-protectedα-amino acid esters of general formula (1) can be represented byfollowing general formula (6):

wherein R² and R³ independently represent an unsubstituted orsubstituted aryl group or lower alkyl group or hydrogen atom, or R² andR³ may be bonded together directly or via a suitable group to form aring structure.

Examples of the ring structures include the following structures (16)and (17):

[Formulae (16) and (17) include both protecting group formed by R² andR³ and the imine structure].

Preferably R² and R³ each represent an unsubstituted or substituted arylgroup or one of them represents an unsubstituted or substituted arylgroup and the other represents a hydrogen atom.

The unsubstituted or substituted lower alkyl group, aralkyl group oraryl group represented by R¹ in the formula in the present inventioninclude unsubstituted or substituted, linear or branched, saturatedalkyl groups having 1 to 8 carbon atoms, unsubstituted or substitutedaralkyl groups having 7 to 15 carbon atoms, and unsubstituted orsubstituted aryl groups having 6 to 14 carbon atoms. R¹ is preferably anunsubstituted or substituted lower alkyl group, or aralkyl group. R¹ isparticularly preferably a linear or branched, saturated alkyl grouphaving 1 to 3 carbon atoms, i.e. methyl group, ethyl group, propylgroup, isopropyl group or unsubstituted or substituted benzyl group.When the benzyl group is substituted, the substituent is an alkoxylgroup (preferably having 1 to 7 carbon atoms), nitro group, an alkylgroup (preferably having 1 to 6 carbon atoms), a halogen atom or thelike.

A in the formulae in the present invention represents a hydrogen atom,an unsubstituted or substituted alkyl group having 1 to 10 carbon atoms,aryl group having 6 to 15 carbon atoms or aralkyl group having 7 to 20carbon atoms, or a corresponding group which further contains a heteroatom in the carbon skeleton. When those groups have a substituent, thesubstituent is an alkoxyl group (preferably having 1 to 7 carbon atoms),a nitro group, an alkyl group (preferably having 1 to 6 carbon atoms), ahalogen atom or the like.

Such a group can be introduced into the compound from, e.g., an aminoacid. For example, when A is hydrogen atom, it can be introduced byusing glycine as the starting material. In the same way, a methyl groupcan be introduced by using alanine; an isopropyl group can be introducedby using valine; a 2-methylpropyl group can be introduced by usingleucine; a 1-methylpropyl group can be introduced by using isoleucine; abenzyl group can be introduced by using phenylalanine; and amethylthioethyl group can be introduced by using methionine.

A may be a group introduced by using an amino acid in which a functionalgroup in a side chain thereof is protected, such as S-t-butylcysteine,S-tritylcysteine, S-(p-methylbenzyl)cysteine,S-(p-methoxybenzyl)cysteine, O-t-butylserine, O-benzylserine,O-t-butylthreonine, O-benzylthreonine, O-t-butyltyrosine orO-benzyltyrosine, as the starting material.

A is not limited to a group introduced from a starting material derivedfrom a natural amino acid, but it may a group introduced from a startingmaterial derived from a synthetic amino acid (such as a cyclohexylmethylgroup, a phenyl group, or a phenylthiomethyl group).

Preferably A represents an unsubstituted or substituted alkyl grouphaving 1 to 10 carbon atoms, aryl group having 6 to 15 carbon atoms oraralkyl group having 7 to 20 carbon atoms, or a group correspondingthereto which contains a hetero atom in the carbon skeleton.

In the formulae in the present invention, X¹ and X² independentlyrepresent a chlorine atom or a bromine atom. It is preferred that bothX¹ and X² represent chlorine atom or bromine atom. It is particularlypreferred that both X¹ and X² represent chlorine atom.

In the formula in the present invention, B³ and B⁴ independentlyrepresent hydrogen atom or a protecting group for amino group, or B³ andB⁴ together form an imine-type protecting group. The protecting groupsfor amino group are as described above. The imine-type protecting groupsare also as described above.

In the formula in the present invention, B⁵ and B⁶ independentlyrepresent a hydrogen atom or a protecting group for an amino group, orB⁵ and B⁶ together form an imine-type protecting group. The protectinggroups for amino group are as described above. The imine-type protectinggroups are also as described above.

N- protected α-amino acid esters of general formula (1) used as thestarting material in the present invention can be produced from α-aminoacid esters and salts thereof or α-amino acids by a known process.

N-carbamate-protected α-amino acid esters particularly preferably usedas the starting compounds in the present invention can be easilysynthesized from α-amino acid esters and salts thereof by an ordinarytechnique of synthesizing peptides.

When N-protected α-amino acid esters of general formula (1) are in aform protected with an imine-type protecting group as shown in abovegeneral formula (6), they can be easily produced from an α-amino acidester of general formula (7) or a salt thereof and an imine compound ofgeneral formula (8) or an aldehyde or ketone compound of general formula(9) by a known method (see, for example, A. Dondoni et al., Synthesis1993, 1162 and M. J. O'Donnel et al., J. Org. Chem. 1982, 47, 2663)according to the following scheme:

wherein R¹, R², R³ and A are as defined above.

The production process of the present invention can be employed forsynthesizing optically active compounds by using an optically activeα-amino acid ester obtained by esterifying an optically active aminoacid. Optically active amino acids are important in the field ofmedicines. Namely, optically active compounds (L- and D-compounds) arepreferably used as the α-amino acid esters. In particular, opticallyactive phenylalanine esters are important starting materials of HIVprotease inhibitors.

Now, the description will be made on the process for producingα-amino-dihalogenated methyl ketones of general formula (3) by reactingan N-protected α-amino acid ester of general formula (1) with adihalomethyl lithium of general formula (2).

A dihalomethyl lithium of general formula (2) can be produced from adihalomethane of general formula (10) and a lithium amide of generalformula (11) according to the following scheme:

wherein X¹ and X² are as defined above, R⁴ and R⁵ independentlyrepresent an alkyl group or a trialkylsilyl group and R⁴ and R⁵ may bebonded together directly or via a suitable group to form a ringstructure.

Examples of the alkyl groups include a methyl group, an ethyl group, anisopropyl group, and a cyclohexyl group. The trialkylsilyl groupsinclude, for example, a trimethylsilyl group. An example of the ringstructures is shown by the following formula (12):

The dihalomethane of general formula (10) is any of dichloromethane,dibromomethane and bromochloromethane. Preferred examples of the lithiumamides of general formula (11) include lithium dimethylamide, lithiumdiethylamide, lithium diisopropylamide, lithium dicyclohexylamide,lithium 2,2,6,6-tetramethyl piperidide and lithiumbis(trimethylsilyl)amide. Lithium diisopropylamide is particularlypreferred.

It is known from U.S. Pat. No. 5,481,011 and Tetrahedron Letters, 38,3175-3178, 1997 that an N-protected α-amino acid ester is reacted withchloroiodomethane and lithium diisopropylamide to form N-protectedα-amino-monochloromethyl ketone. In this reaction, an exchange reactionof an iodine atom with lithium must be carried out in the obtainedintermediate in order to obtain monochloromethyl ketone (see thereaction scheme on page 3175 of the above-described TetrahedronLetters).

According to the Tetrahedron Letters publication (38, 3175-3178, 1997),at least 4 equivalents of chloroiodomethane and also at least 4equivalents of lithium diisopropylamide are [necessitated] necessary. Itis described therein that for attaining the optimum conditions, 4equivalents of chloroiodomethane and 5 equivalents of lithiumdiisopropylamide are to be used.

In the present invention, such an exchange reaction must be preventedfor synthesizing N-protected α-amino-dihalomethyl ketones. Namely, inthe present invention, the amount of a dihalomethyl lithium(particularly dibromomethyl lithium or bromochloromethyl lithium) to bereacted with an N-protected α-amino acid ester is preferably 2equivalents to less than 3 equivalents, more preferably 2.2 equivalentsto 2.8 equivalents, particularly 2.4 equivalents to 2.6 equivalents.

Therefore, in the production of a dihalomethyl lithium from adihalomethane and a lithium amide, the amount of each of dihalomethaneand lithium amide is preferably 2 equivalents to less than 3equivalents, more preferably 2.2 equivalents to 2.8 equivalents,particularly 2.4 equivalents to 2.6 equivalents.

In the production of an N-protected α-amino-dihalomethyl ketone from anN-protected α-amino acid ester and dichloromethyllithium, theabove-described exchange reaction does not occur.

In the dihalomethyl lithiums, dichloromethyl lithium can be producedfrom dichloromethane and an organic lithium of general formula (13)according to the following scheme:

wherein R⁶ represents a lower alkyl group or an aryl group.

The lower alkyl groups include a linear or branched, saturated alkylgroups having 1 to 8 carbon atoms. Linear, saturated alkyl groups having1 to 6 carbon atoms, i.e. a methyl group, an ethyl group, an n-butylgroup, a sec-butyl group, and a n-hexyl group, are particularlypreferred.

The aryl groups are, for example, a phenyl group and a naphthyl group.

Lower alkyllithiums of the above formula wherein R⁶ represents a loweralkyl group are preferred. Those where R⁶ represents a linear, saturatedalkyl group having 1 to 6 carbon atoms, i.e. a methyl group, an ethylgroup, an n-butyl group, a sec-butyl group, and a n-hexyl group, areparticularly preferred.

The N-protected α-amino acid ester is reacted with the dihalomethyllithium.

The following two reaction procedures are possible:

(1) A dihalomethyl lithium is previously produced by reacting a lithiumamide or an organic lithium compound with a dihalomethane. Then, anN-protected α-amino acid ester is added thereto. When both B¹ and B²,which are protecting groups for amino group, are not hydrogen [atom]atoms, this reaction procedure is preferred. The reaction temperature ispreferably about −120° C. to −50° C.

(2) A dihalomethane is reacted with a lithium amide or an organiclithium compound in the presence of an N-protected α-amino acid ester toform a dihalomethyllithium in the reaction system. The reactiontemperature is preferably about −120° C. to +10° C. The reaction can becarried out at a relatively high temperature such as −20° C.

When this reaction procedure is employed, a carbamate-type protectinggroup is preferred.

The reaction solvent is preferably an ether solvent such astetrahydrofuran, diethyl ether, or t-butyl methyl ether. If necessary,the solvent can be used in the form of a mixture thereof with anon-polar solvent, such as toluene or hexane. The reaction rapidlyproceeds at a temperature of about −120° C. to +10° C. Usually, thereaction is completed at −80° C. to −20° C. in 5 to 60 minutes. Afterthe completion of the reaction, the reaction mixture is treated with anaqueous ammonium chloride solution, a phosphate buffer, a dilutehydrochloric acid solution, a dilute sulfuric acid solution, or thelike.

The protecting group for the amino group is either removed or notremoved depending on the combination of the reaction conditions with theprotecting group. The amino group may be kept as it is without theprotecting group or another protecting group may be introduced by awell-known method. The carbamate-type protecting group preferably usedin the present invention can be usually kept as it is when the compoundis reacted as will be described in the Examples given below.

Then, the reaction product is extracted from the reaction solution witha solvent such as ethyl acetate, diethyl ether, toluene, isopropylacetate, tert-butyl methyl ether, dichloromethane, or chloroform. Then,if necessary, the obtained solution is concentrated (or evaporated). Ifnecessary, a solvent such as methanol, ethanol, 2-propanol,acetonitrile, tetrahydrofuran, hexane, heptane or acetone is added tothe product. The obtained solution is heated to about 40 to 80° C. Theα-amino-dihalogenated methyl ketone derivative can be obtained in solidform by the crystallization by cooling to a temperature of −20° C. toroom temperature or by a chromatography. The product may be used for thesubsequent reaction without being separated or purified.

α-Amino-dihalogenated methyl ketone derivatives of general formula (3)can be easily converted into, β-amino-α-hydroxycarboxylic acidderivatives by hydrolysis in the presence of a base, as described in J.P. KOKAI No. Hei 10-59909. In this case, the protecting group for theamino group is either removed or kept depending on the combination ofthe reaction conditions with the protecting group. The compound thusobtained may be isolated as it is without the protecting group oranother protecting group may be introduced. When another protectinggroup is introduced, the introduction can be conducted by, for example,a process described in J. P. KOKAI No. Hei 10-59909.β-amino-α-hydroxycarboxylic acid derivatives are important compounds asintermediates for enzyme inhibitors, such as HIV protease and rennin, orsome anticancer drugs.

The compounds in the present invention also include racemic compoundsand both optically active compounds. When an optically activeN-protected α-amino acid ester is used as the N-protected α-amino acidester of general formula (1), a compound of general formula (3) obtainedby the process of the present invention maintains its optical activity.Further, compounds of general formula (4) produced from theabove-described compounds of general formula (3) also maintain theiroptical activity. Therefore, the process of the present invention isvery useful for the synthesis of intermediate compounds for medicines.

The following Examples will further illustrate the present invention,which by no means limit the invention.

EXAMPLES Reference Example 1 A Process for Producing Methyl Ester ofN-tert-butoxycarbonyl-L-phenylalanine

L-Phenylalanine methyl ester hydrochloride (21.6 g) was added to a mixedsolution of methanol (50 ml) and water (100 ml). Sodium carbonate (11.64g) and then a solution of di-tert-butoxy dicarbonate (21.8 g) inmethanol (100 ml) were added to the obtained mixture. They were heatedto 40° C. and stirred for 6 hours. The reaction mixture was concentratedand the methanol was evaporated. The ethyl [Ethyl] acetate and waterwere added to the obtained concentrate to conduct the extraction. Ethylacetate layer thus obtained was washed with 0.1 N hydrochloric acid,water, an aqueous sodium hydrogencarbonate solution and a saturatedaqueous sodium chloride solution. The obtained ethyl acetate layer wasdried over anhydrous magnesium sulfate. Magnesium sulfate was filteredout. The solvent was evaporated under reduced pressure to obtain theintended methyl ester of N-tert-butoxycarbonyl-L-phenylalanine (26.4 g)in a yield of 95%.

¹H-NMR(CDCl₃, 300 MHz) δ ppm: 1.39 (s, 9H), 2.98-3.16 (m, 2H), 3.69 (s,3H), 4.54-4.65 (m, 1H), 4.93-5.03 (bd, 1H), 7.08-7.32 (m, 5H)

Example 1 A Process for Producing(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone

Dehydrated tetrahydrofuran (15 ml) was cooled to −78° C. 2M solution(5.75 ml) of lithium diisopropylamide in heptane, tetrahydrofuran andethylbenzene was added thereto. A solution of methylene chloride (0.74ml) in dehydrated tetrahydrofuran (5 ml) was added to the obtainedmixture. They were stirred for 10 minutes. Then a solution ofN-tert-butoxycarbonyl-L-phenylalanine methyl ester (1.4 g) in dehydratedtetrahydrofuran (7 ml) was added to the mixture, and they were stirredfor 1 hour. 1 N hydrochloric acid (25 ml) was added to the reactionmixture to terminate the reaction. The temperature was elevated to roomtemperature. After the extraction with ethyl acetate and water, theobtained solution in ethyl acetate was analyzed by HPLC to find that theintended(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (1.31g) was obtained in a yield of 79%. After HPLC with an optically activecolumn, the optical purity of(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone in theethyl acetate solvent was found to be >99.5% e.e. The obtained solutionin ethyl acetate was dried over anhydrous magnesium sulfate. Magnesiumsulfate was filtered off. The solvent was evaporated under reducedpressure. Ethyl acetate was added to the residue to form a slurry. Thecrystals thus formed were separated from the slurry and dried to obtainthe intended (3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (1.12 g) in a yield of 67%.

The obtained(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone wasanalyzed by HPLC with an optically active column to find that theoptical purity thereof was >99.5% e.e.

¹H-NMR(CDCl₃, 300 MHz) δ ppm: 1.40(s,9H), 3.01 (dd,J=7.9, 13.8 Hz, 1H),3.22 (dd,J=5.7, 13.8 Hz, 1H), 4.62-5.00 (m, 2H), 6.08(s, 1H),7.17-7.22(m, 2H), 7.22-7.36(m, 3H) [α] _(D) ²⁰=−52.7° (c=2.25, CH₂Cl₂)

Example 2 A Process for producing(3S)-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone

Methyl ester (1.4 g) of N-tert-butoxycarbonyl-L-phenylalanine (1.4 g)was dissolved in dehydrated tetrahydrofuran (20 ml), and the obtainedsolution was cooled to −78° C. Methylene chloride (0.64 ml) and then 2 Msolution (7.5 ml) of lithium diisopropylamide in heptane,tetrahydrofuran and ethylbenzene were added thereto, and they werestirred for 1 hour. A saturated aqueous ammonium chloride solution (20ml) was added to the reaction mixture to terminate the reaction. Thetemperature was elevated to room temperature. After the extraction withethyl acetate and water, the obtained solution in ethyl acetate wasanalyzed by HPLC to find that the intended(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (0.86g) was obtained in a yield of 52%. The obtained solution in ethylacetate was dried over anhydrous magnesium sulfate. Magnesium sulfatewas filtered off. The solvent was evaporated under reduced pressure.Ethyl acetate was added to the residue to form a slurry. The crystalsthus formed were separated from the slurry and dried to obtain theintended(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (0.65g) in a yield of 36%.

The obtained(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone wasanalyzed by HPLC with an optically active column to find that theoptical purity thereof was >99.5% e.e.

Example 3 A Process for Producing(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone

Methyl ester (1.40 g) of N-tert-butoxycarbonyl-L-phenylalanine wasdissolved in dehydrated tetrahydrofuran (27 ml) and methylene chloride(0.80 ml), and the obtained solution was cooled to −20° C. 2M solution(6.25 ml) of lithium diisopropylamide in heptane, tetrahydrofuran andethylbenzene were added thereto, and they were stirred for 1 hour. 2 NHydrochloric acid (12.5 ml) and water (12.5 ml) were added to thereaction mixture to terminate the reaction. The temperature was elevatedto room temperature. After the extraction with ethyl acetate and water,the obtained solution in ethyl acetate was analyzed by HPLC to find thatthe intended(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (0.94g) was obtained in a yield of 57%. The obtained solution in ethylacetate was dried over anhydrous magnesium sulfate. Magnesium sulfatewas filtered off. The solvent was evaporated under reduced pressure.Ethyl acetate was added to the residue to form a slurry. The crystalsthus formed were separated from the slurry and dried to obtain theintended(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (0.77g) in a yield of 46%.

The obtained(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone wasanalyzed by HPLC with an optically active column to find that theoptical purity thereof was >99.5% e.e.

Example 4 A Process for Producing(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone

Dehydrated tetrahydrofuran (19.5 ml) was cooled to −78° C. 1.53 Msolution (13.1 ml) of n-butyllithium in hexane was added thereto. Asolution of methylene chloride (1.28 ml) in dehydrated tetrahydrofuran(6.9 ml) was added to the obtained mixture and they were stirred for 10minutes. A solution of methyl ester (1.40 g) ofN-tert-butoxycarbonyl-L-phenylalanine in dehydrated tetrahydrofuran (6.9ml) was added thereto and they were stirred for 1 hour. 10% aqueoussulfuric acid solution (10.7 ml) was added to the reaction mixture toterminate the reaction. The temperature was elevated to roomtemperature. After the extraction with ethyl acetate, the obtainedsolution in ethyl acetate was analyzed by HPLC to find that the intended(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (1.00g) was obtained in a yield of 60%. The obtained(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone inethyl acetate solvent was analyzed by HPLC with an optically activecolumn to find that the optical purity thereof was >99.5% e.e. Theobtained solution in ethyl acetate was dried over anhydrous magnesiumsulfate. Magnesium sulfate was filtered off. The solvent was evaporatedunder reduced pressure. Ethyl acetate was added to the residue to form aslurry. The crystals thus formed were separated from the slurry anddried to obtain the intended (3S)-3-tert-butoxycarbonylamino-1,1dichloro-4-phenyl-2-butanone (0.90 g) in a yield of 54%.

Example 5 A Process for Producing(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone

Methyl ester (1.40 g) of N-tert-butoxycarbonyl-L-phenylalanine wasdissolved in dehydrated tetrahydrofuran (33.3 ml). Methylene chloride(1.28 ml) was added to the obtained solution and they were cooled to−78° C. 1.53 M solution (13.1 ml) of n-butyllithium in hexane was addedthereto and they were stirred for 1 hour. 10% aqueous sulfuric acidsolution (10.7 ml) was added to the reaction mixture to terminate thereaction. The temperature was elevated to room temperature. After theextraction with ethyl acetate, the obtained solution in ethyl acetatewas analyzed by HPLC to find that intended(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (1.03g) was obtained in a yield of 62%. The obtained(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone inethyl acetate solvent was analyzed by HPLC with an optically activecolumn to find that the optical purity thereof was >99.5% e.e. Theobtained solution in ethyl acetate was dried over anhydrous magnesiumsulfate. Magnesium sulfate was filtered off. The solvent was evaporatedunder reduced pressure. Ethyl acetate was added to the residue to form aslurry. The crystals were separated from the slurry and dried to obtainthe intended(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (0.87g) in a yield of 52%.

Example 6 A Process for Producing(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone

A mixed solution of dehydrated tetrahydrofuran (6.4 ml) and diethylether (7 ml) was cooled to −78° C. 1.53 M solution (6.5 ml) ofn-butyllithium in hexane was added to the mixed solution and they werestirred for 10 minutes (reaction solution A).

Methyl ester (1.40 g) of N-tert-butoxycarbonyl-L-phenylalanine wasdissolved in a mixture of dehydrated tetrahydrofuran (6.4 ml) anddiethyl ether (7 ml), and the obtained mixture was cooled to −78° C.1.53 M solution (3.3 ml) of n-butyllithium in hexane was added to themixture. Trimethylsilane (0.72 ml) was added to the obtained mixture andthe temperature was elevated to room temperature (reaction solution B).

Reaction solution B was added to reaction solution A, and they werestirred at −78° C. for 1.5 hours (reaction solution C). Saturatedaqueous ammonium chloride solution (20 ml) was added to reactionsolution C to terminate the reaction. The temperature was elevated toroom temperature. After the extraction with ethyl acetate and water, theobtained solution in ethyl acetate was analyzed by HPLC to find that theintended(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (0.88g) was obtained in a yield of 53%. The obtained solution in ethylacetate solvent was dried over anhydrous magnesium sulfate. Magnesiumsulfate was filtered out. The solvent was evaporated under reducedpressure. A mixed solvent of ethyl acetate and n-hexane was added to theresidue to obtain a slurry. Crystals thus obtained were separated anddried to obtain the intended(3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (0.65g) in a yield of 39%. This compound was analyzed by HPLC with anoptically active column to find that the optical purity thereofwas >99.5% e.e.

Example 7 A Process for Producing(2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutanoic acid

(3S)-3-Tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butan one (1.71g) was added to toluene (13 ml), and they were stirred at roomtemperature. 2 N Aqueous sodium hydroxide solution (12.9 ml) was addedto the obtained mixture, and they were stirred at 50° C. for 1 hour.After cooling to room temperature, the aqueous layer was separated. Thetoluene layer was washed with water (5 ml), and the obtained aqueouslayers were combined together and then analyzed by HPLC to find that the3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutanoic acid (1.20 g) wasobtained in a yield of 79%. According to the HPLC analysis, the ratio ofintended (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutanoicacid to its isomer (2R,3S) was as follows: (2S,3S):(2R,3S)=76.6:23.4.6 NHydrochloric acid was added to the aqueous layer to control pH at 2.4.After the extraction with ethyl acetate twice, the obtained ethylacetate layers were combined together and washed with saturated aqueoussodium chloride solution. The obtained solution in ethyl acetate wasdried over anhydrous magnesium sulfate. Magnesium sulfate was filteredout. The solvent was evaporated under reduced pressure. Ethyl acetate(13 ml) was added to the residue and they were heated to 65° C. toobtain a solution. n-Hexane (8 ml) was added to the obtained solution,and they were slowly cooled to 5° C. to form crystals. The crystals thusobtained were separated and washed with a mixed solution of ethylacetate and hexane. After drying, the intended(2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-2-butanoic acid(0.75 g) was obtained in a yield of 50%. According to HPLC analysis, theratio of (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutanoicacid to its isomer.(2R,3S) in the obtained crystals was as follows:(2S,3S):(2R,3S)=99.6:0.4.(2S,3S)-3-Tert-butoxycarbonylamino-2-hydroxy-4-phenylbutanoic acid thusobtained was analyzed by HPLC with an optically active column to findthat the optical purity thereof was >99.5% e.e.

¹H-NMR(CDCl₃, 300 MHz) δ ppm: 1.40(s,9H), 2.93-3.04(m,2H),4.15(ddd,J=2.2, 7.7, 10.2 Hz, 1H), 4.35 (d, J=2.2 Hz, 1H), 4.90 (bs,1H), 7.20-7.35 (m, 5H) [α] _(D) ²⁰=−17.3° (c=1.0, MeOH)

Example 8 A Process for Producing(3S)-1,1-dibromo-3-tert-butoxycarbonylamino-4-phenyl-2-butanone

Dehydrated tetrahydrofuran (15 ml) was cooled to 78° C. 2M solution(6.25 ml) of lithium diisopropylamide in heptane, tetrahydrofuran andethylbenzene was added thereto. Then a solution of dibromomethane (0.88ml) in dehydrated tetrahydrofuran (5 ml) was added to the obtainedmixture, and they were stirred for 10 minutes.

A solution of methyl ester (1.4 g) ofN-tert-butoxycarbonyl-L-phenylalanine in dehydrated tetrahydrofuran (7ml) was added to the obtained mixture, and they were stirred for 1 hour.1 N hydrochloric acid (25 ml) was added to the reaction mixture toterminate the reaction. The temperature was elevated to roomtemperature. After the extraction with ethyl acetate, the obtainedsolution in ethyl acetate was analyzed by HPLC to find that the intended(3S)-1,3-dibromo-3-tert-butoxycarbonylamino-4-phenyl-2-butanone (1.14 g)was obtained in a yield of 53% The obtained solution in ethyl acetatesolvent was dried over anhydrous magnesium sulfate. Magnesium sulfatewas filtered out. The solvent was evaporated under reduced pressure.Ethyl acetate was added to the residue to obtain a slurry. Crystals thusobtained were separated and dried to obtain the intended(3S)-1,1-dibromo-3-tert-butoxycarbonylamino-4-phenyl-2-butanone (1.04 g)in a yield of 46%.

¹H-NMR(CDCl₃, 300 MHz) δ ppm: 1.41 (s, 9H), 3.04 (dd, J=7.3, 13.8 Hz,1H), 3.20 (dd, J=6.2, 13.8 Hz, 1H), 4.64-5.05 (m, 2H), 6.00 (s, 1H),7.17-7.37 (m, 5H) [α] _(D) ²⁰=−40.6° (c=2.0, CH₂Cl₂)

Example 9 A Process for Producing(2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutanoic acid

(3S)-1,1-Dibromo-3-tert-butoxycarbonylamino-4-phenyl-2-butan one (0.20g) was added to toluene (1.2 ml), and they were stirred at roomtemperature. 2 N Aqueous sodium hydroxide solution (1.2 ml) was added tothe obtained mixture, and they were stirred for additional 3 hours. Thentoluene and water were added to the reaction mixture. The aqueous layerwas separated and analyzed by HPLC to find that3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutanoic acid (0.12 g) wasobtained in a yield of 85%. According to the HPLC analysis, the ratio ofintended (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butanoicacid to its isomer (2R,3S) was as follows: (2S,3S):(2R,3S)=81.5:18.5.

Example 10 A Process for Producing(2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutanoic acid

(3S)-1,1-Dibromo-3-tert-butoxycarbonylamino-4-phenyl-2-butanone (100 mg)was added to toluene (0.595 ml), and they were stirred at roomtemperature. 2 N Aqueous sodium hydroxide solution (0.595 ml) was addedto the obtained mixture, and they were stirred at 50° C. for additional50 minutes. After cooling to room temperature, toluene and water wereadded to the reaction mixture. The aqueous layer was separated andanalyzed by HPLC to find that3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutanoic acid (56 mg) wasobtained in a yield of 80%. According to the HPLC analysis, the ratio ofthe intended(2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butanoic acid toits isomer (2R,3S) was as follows: (2S,3S):(2R,3S)=80.3:19.7.

Referential Example 2 A Process for Producing Methyl Ester ofN-(diphenylmethylene)-L-phenylalanine

Hydrochloride of methyl ester of L-phenylalanine (5.95 g) andbenzophenoneimine (5.00 g) were added to methylene chloride (100 ml),and they were stirred at room temperature overnight. A solid thus formedwas filtered out of the reaction mixture. The filtrate was concentratedunder reduced pressure. Diethyl ether (100 ml) was added to the residue.A solid thus formed was again filtered out of the reaction mixture. Theether layer was washed with water (100 ml) and then dried over anhydrousmagnesium sulfate. Magnesium sulfate was removed, and the solution inether was concentrated to obtain the intended methyl ester ofN-(diphenylmethylene)-L-phenylalanine (9.44 g) in a yield of 99.6%.

1H-NMR(CDCl₃, 300 MHz) δ ppm: 3.17 (dd, J=9.0, 13.5 Hz, 1H), 3.27 (dd,J=3.9, 13.5 Hz, 1H), 3.70 (s, 3H), 4.27 (dd, J=3.9, 9.0 Hz, 1H), 6.58(d, J=9.0 Hz, 2H), 7.01-7.04 (m, 2H), 7.16-7.19 (m, 3H), 7.25-7.41 (m,6H), 7.58 (d, J=6.0 Hz, 2H)

Example 11 A Process for Producing(3S)-1,1-dichloro-3-(diphenylmethylene)amino-4-phenyl-2-butanone

A mixed solution of dehydrated tetrahydrofuran (6.2 ml) and diethylether (3.1 ml) was cooled to −78° C. 1.53 M solution (3.3 ml) ofn-butyllithium in hexane and then a solution of methylene chloride (0.40ml) in dehydrated tetrahydrofuran (3.3 ml) were added to the mixedsolution and they were stirred for 10 minutes. Then a solution of methylester of N-(diphenylmethylene)-L-phenylalanine (0.86 g) in diethyl ether(3.3 ml) was added to the obtained solution. They were stirred for 2hours. Saturated aqueous ammonium chloride solution was added to thereaction solution to terminate the reaction. The temperature waselevated to room temperature. After the addition of water followed bythe extraction with ethyl acetate twice, the obtained solutions in ethylacetate were combined together and washed with saturated aqueous sodiumchloride6solution. The obtained solution in ethyl acetate solvent wasdried over anhydrous magnesium sulfate. Magnesium sulfate was filteredout. The solvent was evaporated under reduced pressure to obtain theintended (3S)-1,1-dichloro-3-(diphenylmethylene)amino-4-phenyl-2-butanone (0.95 g) in a yield of 96%.

1H-NMR(CDCl₃, 300 MHz) δ ppm: 3.12 (dd, J=4.6, 13.2 Hz, 1H), 3.20 (dd,J=8.4, 13.2 Hz, 1H), 4.56 (dd, J=4.6, 8.4 Hz, 1H), 6.52 (d, J=9.9 Hz,2H), 6.53 (s, 1H), 6.96-7.05 (m, 2H), 7.15-7.47 (m, 9H), 7.61 d, J=9.1Hz, 2H)

Referential Example 3 A Process for Producing Benzyl Ester ofN,N-dibenzyl-L-phenylalanine

L-Phenylalanine (16.5 g) and potassium carbonate (27.6 g) were added toa mixed solvent of methanol (100 ml) and water (100 ml). Then, benzylbromide (68.4 g) was added to the obtained mixture, and they werestirred under heating and reflux for 3 hours. The reaction mixture wascooled to room temperature, and poured on ice/water. After theextraction with diethyl ether (300 ml), the obtained solution in diethylether was dried over anhydrous sodium sulfate. Sodium sulfate wasfiltered out. 4 N solution (25 ml) of dioxane in hydrochloric acid wasadded to the obtained solution in diethyl ether. After stirring undercooling on ice followed by the crystallization, the crystals wereseparated and washed with diethyl ether. The obtained crystals wereadded to a mixture of water (100 ml) and toluene (100 ml) to obtain aslurry. After the neutralization with a saturated aqueous sodiumhydrogencarbonate solution followed by the division into layers, theproduct was extracted again with toluene. The obtained toluene layerswere combined together and dried over anhydrous magnesium sulfate.Magnesium sulfate was filtered out and the solvent was evaporated underreduced pressure to obtain the intended benzyl ester ofN,N-dibenzyl-L-phenylalanine (37.06 g) in a yield of 85%.

¹H-NMR(CDCl₃, 300 MHz) δ ppm: 2.99 (dd, J=8.2, 14.0 Hz, 1H), 3.14 (dd,J=14.0, 7.4 Hz, 1H), 3.53 (d, J=14.0 Hz, 1H), 3.71 (t, J=7.8 Hz, 1H),3.92 (d, J=14.0 Hz, 1H), 5.11 (d, J=12.3 Hz, 1H), 5.23 (d, J=12.3 Hz,1H), 6.95-7.40 (m, 20H) Mass spectrum m/e: 436 (MH+)

Example 12 A Process for Producing(3S)-1,1-dichloro-3-dibenzylamino-4-phenyl-2-butanone

Dehydrated tetrahydrofuran (15 ml) was cooled to −78° C. 1.53 M solution(6.5 ml) of n-butyllithium in hexane and then a solution of methylenechloride (0.8 ml) in dehydrated tetrahydrofuran (5 ml) were addedthereto, and they were stirred for 10 minutes. A solution of benzylester (2.18 g) of N,N-dibenzyl-L-phenylalanine in dehydratedtetrahydrofuran (7 ml) was added to the obtained mixture, and they werestirred for 1 hour. 2 N hydrochloric acid (15 ml) and water (15 ml) wereadded to the reaction mixture to terminate the reaction. The temperaturewas elevated to room temperature. After the addition of water followedby the extraction with ethyl acetate, the obtained solutions in ethylacetate were combined together and dried over anhydrous magnesiumsulfate. Magnesium sulfate was filtered out. The solvent was evaporatedunder reduced pressure to obtain the intended(3S)-1,1-dichloro-3-dibenzylamino-4-phenyl-2-butanone (2.04 g) in ayield of 99%.

¹H-NMR(CDCl₃, 300 MHz) δ ppm: 3.04 (dd, J=3.8, 13.5 Hz, 1H), 3.23 (dd,J=9.6, 13.5 Hz, 1H), 3.54 (d, J=13.3 Hz, 2H), 3.83 (d, J=13.3 Hz, 2H),3.95 (dd, J=3.8, 9.6 Hz, 1H), 6.14 (d, 1H), 7.12-7.40 (m, 15H)

According to the present invention, α-amino-dihalogenated methyl ketonederivatives and β-amino-α-hydroxycarboxylic acid derivatives can beefficiently produced at a low cost from N-protected α-amino acid esters.Because the optical activity can be kept, the process of the presentinvention is particularly suitable for producing intermediates ofmedicines having structures derived from optically active amino acids.

What is claimed is:
 1. A process for Producing an α-amino-dihalogenatedmethyl ketone of formula (3):

wherein either B³ or B⁴ is a carbamate-type protecting group and theother is a hydrogen atom; A represents a hydrogen atom, an unsubstitutedalkyl group having 1 to 10 carbon atoms, a substituted alkyl grouphaving 1 to 10 carbon atoms, an unsubstituted aryl group having 6 to 15carbon atoms, a substituted aryl group having 6 to 15 carbon atoms anunsubstituted aralkyl group having 7 to 20 carbon atoms, a substitutedaralkyl group having 7 to 20 carbon atoms, or a group correspondingthereto which contains a hetero atom in the carbon skeleton; and X¹ andX² independently represent a chlorine atom or a bromine atom, whichcomprises reacting an N-protected α-amino acid ester of formula (1):

wherein either B¹ or B² is a carbamate-type protecting group and theother is a hydrogen atom, R¹ represents an unsubstituted lower alkylgroup, substituted lower alkyl group, an unsubstituted aralkyl group, asubstituted aralkyl group, a substituted aryl group or an unsubstitutedaryl group, and A is as defined above

 with a dihalomethyl lithium of formula (2) wherein X¹ and X² are asdefined above.
 2. The process according to claim 1, wherein both X¹ andX² are a chlorine atom or a bromine atom.
 3. The process according toclaim 1, wherein both X¹ and X² are a chlorine atom.
 4. The processaccording to claim 1, wherein A is a benzyl group.
 5. The processaccording to claim 1, wherein R¹ is an unsubstituted lower alkyl group,a substituted lower alkyl group, an unsubstituted aralkyl group, or asubstituted aralkyl group and A is an unsubstituted alkyl group or asubstituted alkyl group having 1 to 10 carbon atoms, an unsubstitutedaryl group having 6 to 15 carbon atoms, a substituted aryl group having6 to 15 carbon atoms, an unsubstituted aralkyl group having 7 to 20carbon atoms, a substituted aralkyl group having 7 to 20 carbons, or acorresponding group which further contains a hetero atom in the carbonskeleton.
 6. A process for producing a β-amino-α-hydroxycarboxylic acidof formula (4):

wherein B⁵ and B⁶ independently represent a hydrogen atom or an aminoprotecting group, or B⁵ and B⁶ together form an imine-type protectinggroup, and A represents a hydrogen atom, an unsubstituted alkyl grouphaving 1 to 10 carbon atoms, a substituted alkyl group having 1 to 10carbon atoms, an unsubstituted aryl group having 6 to 15 carbon atoms, asubstituted aryl group having 6 to 15 carbon atoms, an unsubstitutedaralkyl group having 7 to 20 carbon atoms, a substituted aralkyl grouphaving 7 to 20 carbon atoms, or a group corresponding thereto whichcontains a hetero atom in the carbon skeleton, which comprises reactingan N-protected α-amino acid ester of formula (1):

wherein B¹ and B² independently represent a hydrogen atom or an aminoprotecting group, or B¹ and B² together form an imine-type protectinggroup, wherein B¹ and B² are not a hydrogen atom at the same time, R¹represent an unsubstituted lower alkyl group, a substituted lower alkylgroup, an unsubstituted aralkyl group, a substituted aralkyl group, asubstituted aryl group, or an unsubstituted aryl group, and A is asdefined above with a dihalomethyl lithium of formula (2):

wherein X¹ and X² independently represent a chlorine atom or a bromineatom to form an α-amino-dihalogenated methyl ketone of formula (3):

wherein B³ and B⁴ independently represent a hydrogen atom or an aminoprotecting group, or B³ and B⁴ together form an imine-type protectinggroup, and A, X¹ and X² are as defined above; and hydrolyzing in thepresence of a base the α-amino-dihalogenated methyl ketone of formula(3).
 7. The process according to claim 6, herein both X¹ and X² are achlorine atom or a bromine atom.
 8. The process according to claim 6,wherein both X¹ and X² are a chlorine atom.
 9. The process according toclaim 6, wherein either B¹ or B² is a carbamate-type protecting groupand the other is a hydrogen atom, either B³ or B⁴ is a carbamate-typeprotecting group and the other is a hydrogen atom, and either B⁵ or B⁶is a carbamate-type protecting group and the other is a hydrogen atom.10. The process according to claim 6, wherein A is a benzyl group. 11.The process according to claim 6, wherein R¹ is an unsubstituted loweralkyl group, substituted lower alkyl group, an unsubstituted aralkylgroup, or a substituted aralkyl group, and A is an unsubstituted alkylgroup having 1 to 10 carbon atoms, a substituted alkyl group having 1 to10 carbon atoms, an unsubstituted aryl group having 6 to 15 carbonatoms, a substituted aryl group having 6 to 15 carbon atoms, anunsubstituted aralkyl group having 7 to 20 carbon atoms, or asubstituted aralkyl group having 7 to 20 carbon atoms, or a groupcorresponding thereto which contains a hetero atom in the carbonskeleton.
 12. The process according to claim 1, wherein X¹ and X² are abromine atom.
 13. The process according to claim 12, wherein at least 2molar equivalents to 3 molar equivalents of a dihalomethyl lithium permolar equivalent of the N-protected α-amino acid ester are employed. 14.The process according to claim 1, wherein one of X¹ and X² is a bromineatom and the other is a chlorine atom.
 15. The process according toclaim 14, wherein at least 2 molar equivalents to 3 molar equivalents ofa dihalomethyl lithium per molar equivalent of the N-protected α-aminoacid ester are employed.
 16. The process according to claim 6, whereinX¹ and X² are a bromine atom.
 17. The process according to claim 16,wherein at least 2 molar equivalents to 3 molar equivalents of adihalomethyl lithium per molar equivalent of the N-protected α-aminoacid ester are employed.
 18. The process according to claim 6, whereinone of X¹ and X² is a bromine atom and the other is a chlorine atom. 19.The process according to claim 6, wherein at least 2 molar equivalentsto 3 molar equivalents of a dihalomethyl lithium per molar equivalent ofthe N-protected α-amino acid ester are employed.